EP1991541B1 - Neue pyronindolderivate und verfahren zu ihrer herstellung - Google Patents

Neue pyronindolderivate und verfahren zu ihrer herstellung Download PDF

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EP1991541B1
EP1991541B1 EP07733884.6A EP07733884A EP1991541B1 EP 1991541 B1 EP1991541 B1 EP 1991541B1 EP 07733884 A EP07733884 A EP 07733884A EP 1991541 B1 EP1991541 B1 EP 1991541B1
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ring
pyrone
compound
methoxy
ethyl
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EP1991541A2 (de
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Moshe Laudon
Tal Peleg-Shulman
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Neurim Pharmaceuticals 1991 Ltd
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Neurim Pharmaceuticals 1991 Ltd
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Claims (15)

  1. Verbindung der Formel:
    Ar-B-Ar' (I),
    wobei:
    -B- für:
    -X-Y-Z- steht, wobei
    X für -(CH2)n (wobei n 0-6 bedeutet) steht, wobei die Alkylgruppe linear oder verzweigt ist;
    Y für Sauerstoff, Schwefel oder >NH steht oder fehlt;
    Z für >C=O, >O oder >COO steht oder fehlt;
    wobei mindestens eine der Gruppen X, Y und Z vorhanden sein muss;
    Ar für ein Indolkern-Ringsystem steht:
    Figure imgb0032
    Ar' für ein alpha-, beta- oder gamma-Pyronkern-Ringsystem steht:
    Figure imgb0033
     oder
    Figure imgb0034
     oder
    Figure imgb0035
     wobei jeder der Reste R1-4 das Ringsystem Ar in einer beliebigen Position (einschließlich der N-Position) substituiert und jeder der Reste R1'-R2' das Ringsystem Ar' in einer beliebigen Position substituiert, wobei jeder der Reste R1-4 und R1'-2' unabhängig voneinander für Wasserstoff, Sauerstoff, Halogen, Halogen-C1-5-alkyl, Aryl, Acyl, eine C5-7-Heterocyclylgruppe mit 1-3 Heteroatomen, die unabhängig voneinander aus Stickstoff, Sauerstoff oder Schwefel ausgewählt sind; eine C6-8-Heteroarylgruppe mit 1-3 Heteroatomen, die unabhängig voneinander aus Stickstoff, Sauerstoff oder Schwefel ausgewählt sind, C1-5-Alkyl, C2-5-Alkenyl, C2-5-Alkinyl, Aryl-C1-5-alkyl, Aryl-C2-5-alkenyl, Aryl-C2-5-alkinyl, Hydroxy-C1-5-alkyl, Nitro, Amino, Cyano, Cyanamido, Guanidino, Amidino, Acylamido, C1-5-Alkylamin, C1-5-Alkylamido, Hydroxy, Thiol, Acyloxy, Azido, C1-5-Alkoxy, Carboxy, Carbonylamido oder Styryl steht; wobei die Arylalkyl-, Arylalkenyl-, Arylalkinyl- oder Styrylgruppe gegebenenfalls durch einen oder vier Substituenten, die unabhängig voneinander aus der Gruppe bestehend aus Wasserstoff, Halogen, Halogen-C1-5-alkyl, Aryl, einer C5-7-Heterocyclylgruppe mit 1-3 Heteroatomen, die unabhängig voneinander aus Stickstoff, Sauerstoff oder Schwefel ausgewählt sind; einer Heteroarylgruppe mit 1-3 Heteroatomen, die unabhängig voneinander aus Stickstoff, Sauerstoff oder Schwefel ausgewählt sind, C1-5-Alkyl, C2-5-Alkenyl, C2-5-Alkinyl, Aryl-C1-5-alkyl , Aryl-C2-5-alkenyl, Aryl-C2-5-alkinyl, Hydroxy-C1-5-alkyl, Nitro, Amino, Cyano, Cyanamido, Guanidino, Amidino, Acylamido, Hydroxy, Thiol, Acyloxy, Azido, Alkoxy, Carboxy, Carbonylamido S-Alkyl oder Alkylthiol ausgewählt sind, ringsubstituiert sein kann;
    und jeder der Reste R3 oder R4 ferner eine Bindung an B enthalten oder für eine Bindung an B stehen kann;
    wobei Ar in einer beliebigen Position am Ar-Ring, die nicht durch R1 und R2 substituiert ist, einschließlich der N-Position an B gebunden sein kann und Ar' an einem beliebigen Kohlenstoff am Ar'-Ring, der nicht durch R1' und R2' substituiert ist, an B gebunden sein kann;
    oder ein pharmazeutisch unbedenkliches Salz oder Stereoisomer davon;
    wobei es sich bei der Verbindung nicht um:
    Figure imgb0036
     handelt.
  2. Verbindung nach Anspruch 1, wobei X für -(CH2)n steht, wobei n 0-6 bedeutet, Y für >NH oder >O steht und Z für >CO steht.
  3. Verbindung nach Anspruch 2, wobei Ar' für ein alpha-Pyron-Ringsystem steht.
  4. Verbindung nach Anspruch 2, wobei Ar' für ein beta-Pyron-Ringsystem steht.
  5. Verbindung nach Anspruch 2, wobei Ar' für ein gamma-Pyron-Ringsystem steht.
  6. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >NH oder >O steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für Wasserstoff stehen;
    Ar' für einen gamma-Pyronring steht, der an Position 2 des Pyronrings an Z gebunden ist, R1' für Wasserstoff oder eine Hydroxygruppe an Position 5 des Pyronrings steht und R2' für Wasserstoff oder eine Carboxygruppe an Position 6 des gamma-Pyronrings steht;
    oder ein pharmazeutisch unbedenkliches Salz oder Stereoisomer davon.
  7. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >NH oder >O steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für Wasserstoff stehen;
    Ar' für einen alpha-Pyronring steht, der an Position 5 des Pyronrings durch Z substituiert ist, und R1' und R2' jeweis für Wasserstoff stehen;
    oder ein pharmazeutisch unbedenkliches Salz oder Stereoisomer davon.
  8. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >NH steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für Wasserstoff stehen;
    Ar' für einen gamma-Pyronring steht, der an Position 2 des Pyronrings durch Z substituiert ist, R1' für eine Hydroxygruppe an Position 5 des Pyronrings steht und R2' für Wasserstoff steht;
    oder ein Salz oder Stereoisomer davon.
  9. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >O steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für H stehen;
    Ar' für einen gamma-Pyronring steht, der an Position 2 des Pyronrings durch Z substituiert ist, R1' für eine Hydroxygruppe an Position 5 des Pyronrings steht und R2' für Wasserstoff steht;
    oder ein Salz oder Stereoisomer davon.
  10. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >NH steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für Wasserstoff stehen;
    Ar' für einen gamma-Pyronring steht, der an Position 2 des Pyronrings durch Z substituiert ist, und R1' und R2' jeweils für Wasserstoff stehen;
    oder ein Salz oder Stereoisomer davon.
  11. Verbindung nach Anspruch 1, wobei
    X für -(CH2)2- steht, Y für >NH steht und Z für >CO steht,
    Ar für einen Indolring steht; R3 für eine Bindung an X an Position 3 des Indolrings steht; R1 für eine Methoxygruppe an Position 5 des Indolrings steht und R2 und R4 jeweils für H stehen;
    Ar' für einen alpha-Pyronring steht, der an Position 5 des Pyronrings durch Z substituiert ist, und R1' und R2' jeweils für Wasserstoff stehen;
    oder ein Salz oder Stereoisomer davon.
  12. Pharmazeutische Formulierung, umfassend eine therapeutisch wirksame Menge einer Verbindung, eines Salzes oder eines Stereoisomers nach einem der Ansprüche 1 bis 11 in Kombination mit einem oder mehreren pharmazeutisch unbedenklichen Verdünnungsmitteln, Konservierungsmitteln, Lösungsvermittlern, Emulgatoren, Adjuvantien, Exzipienten oder Trägern.
  13. Pharmazeutische Formulierung, umfassend eine wirksame Menge einer Verbindung, eines Salzes oder eines Stereoisomers nach einem der Ansprüche 1 bis 11, zur Verwendung bei der Behandlung oder Prävention von Insulinresistenz, Typ-II-Diabetes, Neuronenverlust in Verbindung mit Schlaganfall, Ischämie, Zentralnervensystemtrauma, einer Störung des Zentralnervensystems, einer neurodegenerativen Erkrankung, den nachteiligen Folgen der Überstimulation von exzitatorischen Aminosäuren, einer psychiatrischen Erkrankung, Epilepsie oder einer anderen konvulsivischen Störung, Angst, Schlafstörungen, chronischen Schmerzen, Glaukom, CMV-Retinitis, Harninkontinenz oder Opiat-Toleranz oder -Entzugssymptomen oder zur Induzierung von Anästhesie oder zur Verbesserung der Kognition bei einem Tier oder einem Menschen, das bzw. der einer derartigen Behandlung bedarf.
  14. Formulierung, umfassend eine wirksame Menge einer Verbindung, eines Salzes oder eines Stereoisomers nach einem der Ansprüche 1 bis 11, zur Verwendung bei der Behandlung oder Prävention von Impotenz, einer Herz-Kreislauf-Störung, Neuropathie, einer entzündlichen Störung, Neuropathie, einer Störung auf chronobiologischer Basis, einer Schlafstörung, die auf den zirkadianen Rhythmus zurückzuführen ist, einer endokrinen Störung, einer neoplastischen Erkrankung, einer Störung des Immunsystems, einem mit Seneszenz assoziierten Leiden, einer ophthalmologishen Erkrankung, Cluster-Headache, Migräne, Gewichtszunahmestörung oder zur Regulierung der Fruchtbarkeit, Pubertät oder Haarkleidfarbe als Hilfsmittel bei der Tierzucht oder zum Schutz der Haut bei einem Tier oder einem Menschen, das bzw. der einer derartigen Behandlung bedarf.
  15. Formulierung, umfassend eine wirksame Menge einer Verbindung, eines Salzes oder eines Stereoisomers nach einem der Ansprüche 1 bis 11, zur Verwendung bei der Änderung des zirkadianen Rhythmus, zur Verbesserung der Schlafqualität oder zur Behandlung oder Prävention einer Schlafstörung bei einem Tier oder einem Menschen, das bzw. der einer derartigen Behandlung bedarf.
EP07733884.6A 2006-02-15 2007-02-13 Neue pyronindolderivate und verfahren zu ihrer herstellung Active EP1991541B1 (de)

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PL07733884T PL1991541T3 (pl) 2006-02-15 2007-02-13 Nowe pochodne pironowo-indolowe i sposób ich otrzymywania
SI200731333T SI1991541T1 (sl) 2006-02-15 2007-02-13 Novi piron-indolinski derivati in postopek za njihovo pripravo

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PCT/IB2007/000330 WO2007093880A2 (en) 2006-02-15 2007-02-13 Novel pyrone-indole derivatives and process for their preparation

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US6262118B1 (en) * 1999-06-04 2001-07-17 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia
CN103319467B (zh) * 2013-06-15 2015-10-14 湖南科技大学 一种4-[5-羟基-4-吡喃酮-2-基亚甲氨基]-3-巯基-1,2,4-三唑化合物及用途
ES2694049T3 (es) 2014-01-14 2018-12-17 Astellas Pharma Inc. Compuesto de indol
RU2561045C1 (ru) * 2014-07-15 2015-08-20 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Кубанский государственный университет" (ФГБОУ ВПО "КубГУ") Нейропротекторное фармакологическое средство
US9567510B2 (en) 2014-09-11 2017-02-14 Halliburton Energy Services, Inc. Cyanamide-based carbon dioxide and/or hydrogen sulfide scavengers and methods of use in subterranean operations
PL3261640T3 (pl) 2015-02-25 2022-10-31 The Regents Of The University Of California Agoniści 5ht do leczenia zaburzeń padaczkowych
JP6910424B2 (ja) * 2016-08-23 2021-07-28 ニューリム・ファーマシューティカルズ・リミテッドＮｅｕｒｉｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ． 掻痒症および／または痒みの治療方法
WO2019028234A1 (en) * 2017-08-04 2019-02-07 Ovid Therapeutics Inc. USE OF GABOXADOL IN THE TREATMENT OF DIABETES AND RELATED CONDITIONS
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US11690829B2 (en) 2018-12-17 2023-07-04 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of non-24 hour sleep-wake disorder
US20230172905A1 (en) * 2020-05-11 2023-06-08 B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University Compositions of tryptophol derivatives and 4-ethyl-phenol derivatives, and methods of using same
EP4337793A1 (de) 2021-05-11 2024-03-20 Neurim Pharmaceuticals (1991) Ltd. Verfahren zur diagnose und behandlung von patienten mit einzelnukleotidpolymorphismen im chromosom 2, 2,7107,510000-107,540000-lokus

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TWI501960B (zh) 2015-10-01
CN101374833B (zh) 2012-06-27
ES2428873T3 (es) 2013-11-12
TW200835690A (en) 2008-09-01
CN101374833A (zh) 2009-02-25
KR101207736B1 (ko) 2012-12-03
WO2007093880A2 (en) 2007-08-23
BRPI0706992B1 (pt) 2021-05-04
BRPI0706992C8 (pt) 2021-05-25
CA2642465A1 (en) 2007-08-23
WO2007093880A3 (en) 2007-11-01
JP5248332B2 (ja) 2013-07-31
US20100048662A1 (en) 2010-02-25
AU2007216226B2 (en) 2011-02-24
PT1991541E (pt) 2013-10-02
NO20083905L (no) 2008-09-12
IL193236A (en) 2012-08-30
DK1991541T3 (da) 2013-10-28
US8242163B2 (en) 2012-08-14
US7635710B2 (en) 2009-12-22
US20080027121A1 (en) 2008-01-31
SI1991541T1 (sl) 2014-02-28
UA104988C2 (uk) 2014-04-10
KR20080094945A (ko) 2008-10-27
US20120302620A1 (en) 2012-11-29
EA200801580A1 (ru) 2009-02-27
NZ569797A (en) 2010-06-25
ZA200806799B (en) 2009-10-28
EP1991541A2 (de) 2008-11-19
HK1126760A1 (en) 2009-09-11
AU2007216226A2 (en) 2009-05-14
EA015605B1 (ru) 2011-10-31
NO339826B1 (no) 2017-02-06
AU2007216226A1 (en) 2007-08-23
JP2009526831A (ja) 2009-07-23
BRPI0706992A2 (pt) 2011-04-12
IL193236A0 (en) 2009-02-11
BRPI0706992C1 (pt) 2021-05-18
PL1991541T3 (pl) 2013-12-31
US8569355B2 (en) 2013-10-29
CA2642465C (en) 2012-08-07

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